This is a patient oriented mentored clinician scientist (K23) grant application. Sai Yendamuri is a thoracic surgeon holding the position of Assistant Professor at the Roswell Park Cancer Institute (RPCI). He has significant experience in microRNA related research and is seeking support for additional time in a mentored setting to develop the skills necessary to transition into an independent translational researcher. Roswell Park Cancer Institute (RPCI) is an NCI designated Comprehensive Cancer Center that fosters clinical care in an environment of translational research. Under the guidance of Dr. Alex Adjei and Dr. Thomas Tomasi, Dr. Yendamuri has developed a comprehensive career training plan that encompasses didactic training in clinical trial design, microarray analysis, bioinformatics and an overview of cancer biology. He will also be mentored by a committee consisting of experts in biomarker research, biostatistics, bioinformatics, microarray studies and non-coding RNA genomics. Lung cancer accounts for more deaths annually than breast cancer, prostate cancer and colon cancer combined. Even for stage I lung cancer, the overall cure rate remains low (5-year survival rates of 65%-75%). This highlights the importance of the development and application of molecular biology techniques for more effective clinical management of this disease. MicroRNAs (miRNAs) have emerged as major mediators of epigenetic regulation and are thought to control at least a third of the human genome. MicroRNA expression profiling has been shown to be useful in prognostication. Recent evidence has demonstrated the stability of miRNA in serum and their promise as biomarkers of physiological and pathological states. This proposal aims to refine a microRNA signature that Dr. Yendamuri recently identified to predict recurrence in patients with stage I lung cancer. This will be performed in a retrospective fashion in a cohort of patients followed by the Cancer and Leukemia Group B. The refined signature will then be prospectively validated in a cohort of patients with early lung cancer at RPCI. Such prognostication will enable the identification of cases for adjuvant chemotherapy to improve the chances of cure while minimizing the risk. The study also attempts to utilize the stability of miRNAs in blood to identify serum microRNAs that can serve as biomarkers of the lung cancer state. This is based upon previous work done by Dr. Yendamuri to optimize RNA extraction from serum and reliably quantitate it using a microarray platform. In this part of the proposal, the investigators will compare blood microRNA profiles of lung cancer patients before and after surgical resection in order to narrow down a set of microRNAs that reflect the presence of lung cancer. This may identify a panel of microRNAs that may serve as biomarkers of the lung cancer state. This proposal is an important step towards the development of personalized cancer therapy and the development of blood based lung cancer biomarkers. Dr. Yendamuri's previous experience with microRNA research, the experience and expertise of the members of the mentoring committee, the availability of the required tissue and resources at RPCI, and the institutional and departmental commitment to the career development of the candidate ensure the viability of the training of the candidate and execution of the proposed experiments. PUBLIC HEALTH RELEVANCE: MicroRNAs are short (18-25 nt) RNAs that are thought to control the expression of at least one third of the human genome. In this project, we propose refining and prospectively validating a microRNA signature to predict recurrence after resection of early lung cancer. We also aim to identify serum microRNAs that can serve as biomarkers of the lung cancer disease state.